Aromatic heterocyclic compounds as antiinflammatory agents

ABSTRACT

Disclosed are novel aromatic heterocyclic compounds of the formula(I) wherein Ar 1 ,Ar 2 ,L,Q and X are described herein. The compounds are useful in pharmaceutic compositions for treating diseases or pathological conditions involving inflammation such as chronic inflammatory diseases. Also disclosed are processes of making such compounds.

RELATED APPLICATION DATA

This application is a divisional of U.S. application Ser. No. 09/484,638filed Jan. 18, 2000 now U.S. Pat. No. 6,319,921, which claims thebenefit of Provisional application Ser. No. 60/116,400, filed Jan. 19,1999.

TECHNICAL FIELD OF THE INVENTION

This invention relates to novel aromatic heterocyclic compounds offormula (I):

wherein Ar₁, Ar₂, X, L and Q are defined below, which inhibit productionof cytokines involved in inflammatory processes and are thus useful fortreating diseases and pathological conditions involving inflammationsuch as chronic inflammatory disease. This invention also relates toprocesses for preparing these compounds and to pharmaceuticalcompositions comprising these compounds.

BACKGROUND OF THE INVENTION

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are importantbiological entities collectively referred to as proinflammatorycytokines. These, along with several other related molecules, mediatethe inflammatory response associated with the immunological recognitionof infectious agents. The inflammatory response plays an important rolein limiting and controlling pathogenic infections. Elevated levels ofproinflammatory cytokines are also associated with a number of diseasesof autoimmunity such as toxic shock syndrome, rheumatoid arthritis,osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C.A., et al., 1984, Rev. Infect. Disease 6:51). In these diseases, chronicelevation of inflammation exacerbates or causes much of thepathophysiology observed. For example, rheumatoid synovial tissuebecomes invaded with inflammatory cells that result in destruction tocartilage and bone (Koch, A. E., et al., 1995, J. Invest. Med. 43:28-38). An important and accepted therapeutic approach for potentialdrug intervention in these diseases is the reduction of proinflammatorycytokines such as TNF (also referred to in its secreted cell-free formtermed TNFα) and IL-1β. A number of anti-cytokine therapies arecurrently in clinical trials. Efficacy has been demonstrated with amonoclonal antibody directed against TNFα in a number of autoimmunediseases (Heath, P., “CDP571: An Engineered Human IgG4 Anti-TNFαAntibody”IBC Meeting on Cytokine Antagonists, Philadelphia, Pa., Apr.24-5, 1997). These include the treatment of rheumatoid arthritis,Crohn's disease and ulcerative colitis (Rankin, E. C. C., et al., 1997,British J. Rheum. 35: 334-342 and Stack, W.A., et al., 1997, Lancet 349:521-524). The monoclonal antibody is thought to function by binding toboth soluble TNFα and to membrane bound TNF.

A soluble TNFα receptor has been engineered that interacts with TNFα.The approach is similar to that described above for the monoclonalantibodies directed against TNFα both agents bind to soluble TNFα, thusreducing its concentration. One version of this construct, called Enbrel(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase IIIclinical trial for the treatment of rheumatoid arthritis (Brower et al.,1997, Nature Biotechnology 15: 1240). Another version of the TNFαreceptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) hasdemonstrated efficacy in various animal models of allergic lunginflammation and acute lung injury. Ro 45-2081 is a recombinant chimericmolecule constructed from the soluble 55 kDa human TNF receptor fused tothe hinge region of the heavy chain IgGl gene and expressed ineukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143). IL-1has been implicated as an immunological effector molecule in a largenumber of disease processes. IL-1 receptor antagonist (IL-1ra) had beenexamined in human clinical trials. Efficacy has been demonstrated forthe treatment of rheumatoid arthritis (Antril, Amgen). In a phase IIIhuman clinical trial IL-1ra reduced the mortality rate in patients withseptic shock syndrome (Dinarello, 1995, Nutrution 11, 492).Osteoarthritis is a slow progressive disease characterized bydestruction of the articular cartilage. IL-1 is detected in synovialfluid and in the cartilage matrix of osteoarthritic joints. Antagonistsof IL-1 have been shown to diminish the degradation of cartilage matrixcomponents in a variety of experimental models of arthritis (Chevalier,1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator ofcardiovascular homeostasis, neurotransmission and immune function;recently it has been shown to have important effects in the modulationof bone remodeling. Cytokines such as IL-1 and TNF are potentstimulators of NO production. NO is an important regulatory molecule inbone with effects on cells of the osteoblast and osteoclast lineage(Evans, et al., 1996, J. Bone Miner Res. 11, 300). The promotion ofbeta-cell destruction leading to insulin dependent diabetes mellitisshows dependence on IL-1. Some of this damage may be mediated throughother effectors such as prostaglandins and thromboxanes. IL-1 can effectthis process by controlling the level of both cyclooxygenase II andinducible nitric oxide synthetase expression (McDaniel et al., 1996,Proc Soc Exp Biol Med. 211, 24).

Inhibitors of cytokine production are expected to block induciblecyclooxygenase (COX-2) expression. COX-2 expression has been shown to beincreased by cytokines and it is believed to be the isoform ofcyclooxygenase responsible for inflammation (M. K. O'Banion et al.,Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 4888.) Accordingly, inhibitorsof cytokines such as IL-1 would be expected to exhibit efficacy againstthose disorders currently treated with COX inhibitors such as thefamiliar NSAIDs. These disorders include acute and chronic pain as wellas symptoms of inflammation and cardiovascular disease.

Elevation of several cytokines have been demonstrated during activeinflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1and IL-1ra is present in patients with IBD. Insufficient production ofendogenous IL-1ra may contribute to the pathogenesis of IBD (Cominelli,et al., 1996, Aliment Pharmacol Ther. 10, 49). Alzheimer disease ischaracterized by the presence of beta-amyloid protein deposits,neurofibrillary tangles and cholinergic dysfunction throughout thehippocampal region. The structural and metabolic damage found inAlzheimer disease is possibly due to a sustained elevation of IL-1(Holden, et al., 1995, Med Hypootheses 45, 559). A role for IL-1 in thepathogenesis of human immunodeficiency virus (HIV) has been identified.IL-1ra showed a clear relationship to acute inflammatory events as wellas to the different disease stages in the pathophysiology of HIVinfection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54). IL-1 andTNF are both involved in periodontal disease. The destructive processassociated with periodontal disease may be due to a disregulation ofboth IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).

Proinflammatory cytokines such as TNFα and IL-1β are also importantmediators of septic shock and associated cardiopulmonary dysfunction,acute respiratory distress syndrome (ARDS) and multiple organ failure.TNFα has also been implicated in cachexia and muscle degradation,associated with HIV infection (Lahdiverta et al., 1988, Amer. J Med.,85, 289). Obesity is associated with an increase incidence of infection,diabetes and cardiovascular disease. Abnormalities in TNFα expressionhave been noted for each of the above conditions (Loffreda, et al.,1998, FASEB J. 12, 57). It has been proposed that elevated levels ofTNFα are involved in other eating related disorders such as anorexia andbulimia nervosa. Pathophysiological parallels are drawn between anorexianervosa and cancer cachexia (Holden, et al., 1996, Med Hypotheses 47,423). An inhibitor of TNFα production, HU-211, was shown to improve theoutcome of closed brain injury in an experimental model (Shohami, etal., 1997, J Neuroimmunol. 72, 169). Atherosclerosis is known to have aninflammatory component and cytokines such as IL-1 and TNF have beensuggested to promote the disease. In an animal model an IL-1 receptorantagonist was shown to inhibit fatty streak formation (Elhage et al.,1998, Circulation, 97, 242).

The abnormal expression of inducible nitric oxide synthetase (iNOS) hasbeen associated with hypertension in the spontaneously hypertensive rat(Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in theexpression of iNOS and therefore may also have a role in thepathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension,9, 867).

IL-1 has also been shown to induce uveitis in rats which could beinhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol.and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have beenshown to stimulate proliferation of acute myelogenous leukemia blasts(Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essentialfor the development of both irritant and allergic contact dermatitis.Epicutaneous sensitization can be prevented by the administration of ananti-IL-1 monoclonal antibody before epicutaneous application of anallergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Dataobtained from IL-1 knock out mice indicates the critical involvement infever for this cytokine (Kluger et al., 1998, Clin Exp PharmacolPhysiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 andIL-8 initiate the acute-phase reaction which is stereotyped in fever,malaise, myalgia, headaches, cellular hypermetabolism and multipleendocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813).The production of these inflammatory cytokines rapidly follows trauma orpathogenic organism invasion.

Other proinflammatory cytokines have been correlated with a variety ofdisease states. IL-8 correlates with influx of neutrophils into sites ofinflammation or injury. Blocking antibodies against IL-8 havedemonstrated a role for IL-8 in the neutrophil associated tissue injuryin acute inflammation (Harada et al., 1996, Molecular Medicine Today 2,482). Therefore, an inhibitor of IL-8 production may be useful in thetreatment of diseases mediated predominantly by neutrophils such asstroke and myocardial infarction, alone or following thrombolytictherapy, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, acute glomerulonephritis,dermatoses with acute inflammatory components, acute purulent meningitisor other central nervous system disorders, hemodialysis, leukopherisis,granulocyte transfusion associated syndromes, and necrotizingentrerocolitis.

Rhinovirus triggers the production of various proinflammatory cytokines,predominantly IL-8, which results in symptomatic illnesses such as acuterhinitis (Winther et al., 1998, Am J Rhinol. 12, 17). Other diseasesthat are effected by IL-8 include myocardial ischemia and reperifusion,inflammatory bowel disease and many others.

The proinflammatory cytokine IL-6 has been implicated with the acutephase response. IL-6 is a growth factor in a number in oncologicaldiseases including multiple myeloma and related plasma cell dyscrasias(Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has alsobeen shown to be an important mediator of inflammation within thecentral nervous system. Elevated levels of IL-6 are found in severalneurological disorders including AIDS dememtia complex, Alzheimer'sdisease, multiple sclerosis, systemic lupus erythematosus, CNS traumaand viral and bacterial meningitis (Gruol, et al., 1997, MolecularNeurobiology 15: 307). IL-6 also plays a significant role inosteoporosis. In murine models it has been shown to effect boneresorption and to induce osteoclast activity (Ershler et al., 1997,Development and Comparative Immunol. 21: 487). Marked cytokinedifferences, such as IL-6 levels, exist in vivo between osteoclasts ofnormal bone and bone from patients with Paget's disease (Mills, et al.,1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shownto be involved in cancer cachexia. The severity of key parameters ofcachexia can be reduced by treatment with anti IL-6 antibodies or withIL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther.1, 107). Several infectious diseases, such as influenza, indicate IL-6and IFN alpha as key factors in both symptom formation and in hostdefense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpressionof IL-6 has been implicated in the pathology of a number of diseasesincluding multiple myeloma, rheumatoid arthritis, Castleman's disease,psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997,Protein Sci. 6, 929). Compounds that interfered with the production ofcytokines including IL-6, and TNF were effective in blocking a passivecutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41,1050).

GM-CSF is another proinflammatory cytokine with relevance to a number oftherapeutic diseases. It influences not only proliferation anddifferentiation of stem cells but also regulates several other cellsinvolved in acute and chronic inflammation. Treatment with GM-CSF hasbeen attempted in a number of disease states including bum-woundhealing, skin-graft resolution as well as cytostatic and radiotherapyinduced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF alsoappears to play a role in the replication of human immunodeficiencyvirus (HIV) in cells of macrophage lineage with relevance to AIDStherapy (Crowe et al., 1997, Journal ofLeukocyte Biology 62, 41).Bronchial asthma is characterised by an inflammatory process in lungs.Involved cytokines include GM-CSF amongst others (Lee, 1998, JR CollPhysicians Lond 32, 56).

Interferon γ (IFN γ) has been implicated in a number of diseases. It hasbeen associated with increased collagen deposition that is a centralhistopathological feature of graft-versus-host disease (Parkman, 1998,Curr Opin Hematol. 5, 22). Following kidney transplantation, a patientwas diagnosed with acute myelogenous leukemia. Retrospective analysis ofperipheral blood cytokines revealed elevated levels of GM-CSF and IFN γ.These elevated levels coincided with a rise in peripheral blood whitecell count (Burke, et al., 1995, Leuk Lymphoma. 19, 173). Thedevelopment of insulin-dependent diabetes (Type 1) can be correlatedwith the accumulation in pancreatic islet cells of T-cells producing IFNγ (Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFN γ along with TNF,IL-2 and IL-6 lead to the activation of most peripheral T-cells prior tothe development of lesions in the central nervous system for diseasessuch as multiple sclerosis (MS) and AIDS dementia complex (Martino etal., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result inarterial disease that can lead to cardiac and cerebral infarction. Manyactivated immune cells are present in these lesions, mainly T-cells andmacrophages. These cells produce large amounts of proinflammatorycytokines such as TNF, IL-1 and IFN γ. These cytokines are thought to beinvolved in promoting apoptosis or programmed cell death of thesurrounding vascular smooth muscle cells resulting in theatherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76).Allergic subjects produce mRNA specific for IFN γ following challengewith Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342).The expression of a number of cytokines, including IFN γ has been shownto increase following a delayed type hypersensitivity reaction thusindicating a role for IFN γ in atopic dermatitis (Szepietowski, et al.,1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologicstudies were performed in cases of fatal cerebral malaria. Evidence forelevated IFN γ amongst other cytokines was observed indicating a role inthis disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501).The importance of free radical species in the pathogenesis of variousinfectious diseases has been established. The nitric oxide synthesispathway is activated in response to infection with certain viruses viathe induction of proinflammatory cytokines such as IFN γ (Akaike, etal., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronicallyinfected with hepatitis B virus (HBV) can develop cirrhosis andhepatocellular carcinoma. Viral gene expression and replication in HBVtransgenic mice can be suppressed by a post-transcriptional mechanismmediated by IFN γ, TNF and IL-2 (Chisari, et al., 1995, Springer SeminImmunopathol. 17, 261). IFN γ can selectively inhibit cytokine inducedbone resorption. It appears to do this via the intermediacy of nitricoxide (NO) which is an important regulatory molecule in bone remodeling.NO may be involved as a mediator of bone disease for such diseases as:the rheumatoid arthritis, tumor associated osteolysis and postmenopausalosteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studieswith gene deficient mice have demonstrated that the IL-12 dependentproduction of IFN γ is critical in the control of early parasiticgrowth. Although this process is independent of nitric oxide the controlof chronic infection does appear to be NO dependent (Alexander et al.,1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an importantvasodilator and convincing evidence exists for its role incardiovascular shock (Kilboum, et al., 1997, Dis Mon. 43, 277). IFN γ isrequired for progression of chronic intestinal inflammation in suchdiseases as Crohn's disease and inflammatory bowel disease (IBD)presumably through the intermediacy of CD4+ lymphocytes probably of theTH1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). Anelevated level of serum IgE is associated with various atopic diseasessuch as bronchial asthma and atopic dermatitis. The level of IFN γ wasnegatively correlated with serum IgE suggesting a role for IFN γ inatopic patients (Teramoto et al, 1998, Clin Exp Allergy 28, 74).

Compounds which modulate release of one or more of the aforementionedinflammatory cytokines can be useful in treating diseases associatedwith release of these cytokines. For example, WO 98/52558 disclosesheteroaryl urea compounds which are indicated to be useful in treatingcytokine mediated diseases.

U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N′-heterocyclicsubstituted urea compounds which are described as being useful fortreating hypercholesterolemia and atheroclerosis.

The work cited above supports the principle that inhibition of cytokineproduction will be beneficial in the treatment of various diseasestates. Some protein therapeutics are in late development or have beenapproved for use in particular diseases. Protein therapeutics are costlyto produce and have bioavailability and stability problems. Therefore aneed exists for new small molecule inhibitors of cytokine productionwith optimized efficacy, pharmacokinetic and safety profiles.

BRIEF SUMMARYOF THE INVENTION

The work cited above supports the principle that inhibition of cytokineproduction will be beneficial in the treatment of various diseasestates.

It is therefore an object of the invention to provide novel compoundswhich inhibit the release of inflammatory cytokines such asinterleukin-1 and tumor necrosis factor.

It is a further object of the invention to provide methods for treatingdiseases and pathological conditions involving inflammation such aschronic inflammatory disease.

It is yet a further object of the invention to provide processes ofpreparation of the above-mentioned novel compounds.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula (I):

wherein

Ar₁ is a heterocyclic group selected from the group consisting ofpyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan andthiophene; and wherein Ar₁ may be substituted by one or more R₁,R₂ orR₃;

Ar₂ is:

phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl,tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran,indanyl, indenyl or indole each being optionally substituted with one tothree R₂ groups;

L, a linking group, is a:

C₁₋₁₀ saturated or unsaturated branched or unbranched carbon chain;

wherein one or more methylene groups are optionally independentlyreplaced by O,N or S; and

wherein said linking group is optionally substituted with 0-2 oxo groupsand one or more C₁₋₄ branched or unbranched alkyl which may besubstituted by one or more halogen atoms;

Q is selected from the group consisting of:

a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole,benzimidazole, furan, thiophene, pyran, naphthyridine,oxazo[4,5-b]pyridine and imidazo[4,5-b]pyridine, which are optionallysubstituted with one to three groups selected from the group consistingof halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, mono- ordi-(C₁₋₃alkyl)amino, C₁₋₆alkyl-S(O)_(m) and phenylamino wherein thephenyl ring is optionally substituted with one to two groups selectedfrom the consisting of halogen, C₁₋₆alkyl and C₁₋₆alkoxy;

b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone,1,4-dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide,thiomorpholine sulfone, piperidine, piperidinone, tetrahydropyrimidone,cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylenesulfoxide, pentamethylene sulfone, tetramethylene sulfide,tetramethylene sulfoxide and tetramethylene sulfone which are optionallysubstituted with one to three groups selected from the group consistingof C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, mono- ordi-(C₁₋₃alkyl)amino-C₁₋₃alkyl, phenylamino-C₁₋₃ alkyl and C₁₋₃alkoxy-C₁₋₃alkyl;

c) C₁₋₆ alkoxy, secondary or tertiary amine wherein the amino nitrogenis covalently bonded to groups selected from the group consisting ofC₁₋₃ alkyl and C₁₋₅ alkoxyalkyl and phenyl wherein the phenyl ring isoptionally substituted with one to two groups consisting of halogen,C₁₋₆ alkoxy, hydroxy or mono- or di-(C₁₋₃ alkyl)amino, C₁₋₆alkyl-S(O)_(r), phenyl-S(O)_(t), wherein the phenyl ring is optionallysubstituted with one to two groups consisting of halogen, C₁₋₆ alkoxy,hydroxy and mono- or di-(C₁₋₃ alkyl)amino;

R₁ is selected from the group consisting of:

(a) C₃₋₁₀ branched or unbranched alkyl, which may optionally bepartially or fully halogenated, and optionally substituted with one tothree phenyl, naphthyl or heterocyclic groups selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; eachsuch phenyl, naphthyl or heterocycle selected from the group hereinabovedescribed, being substituted with 0 to 5 groups selected from the groupconsisting of halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, C₃₋₈ cycloalkyl, C₅₋₈cycloalkenyl, hydroxy, cyano, C₁₋₃ alkyloxy which is optionallypartially or fully halogenated, NH₂C(O) and di(C₁₋₃)alkylaminocarbonyl;

(b) C₃₋₇ cycloalkyl selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl, which may optionally be partially orfully halogenated and which may optionally be substituted with one tothree C₁₋₃ alkyl groups, or an analog of such cycloalkyl group whereinone to three ring methylene groups are replaced by groups independentlyselected from O, S, CHOH, >C═O, >C═S and NH;

(c) C₃₋₁₀ branched alkenyl which may optionally be partially or fullyhalogenated, and which is optionally substituted with one to three C₁₋₅branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups,with each such heterocyclic group being independently selected from thegroup consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl andisothiazolyl, and each such phenyl, naphthyl or heterocyclic group beingsubstituted with 0 to 5 groups selected from halogen, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, cyano,C₁₋₃ alkyloxy which is optionally partially or fully halogenated,NH₂C(O), mono- or di(C₁₋₃)alkylaminocarbonyl;

(d) C₅₋₇ cycloalkenyl selected from the group consisting ofcyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein suchcycloalkenyl group may optionally be substituted with one to three C₁₋₃alkyl groups;

(e) cyano; and,

(f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;

R₂ is selected from the group consisting of:

a C₁₋₆ branched or unbranched alkyl which may optionally be partially orfully halogenated, acetyl, aroyl, C₁₋₄ branched or unbranched alkoxy,which may optionally be partially or fully halogenated, halogen,methoxycarbonyl and phenylsulfonyl;

R₃ is selected from the group consisting of:

a) a phenyl, naphthyl or heterocyclic group selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl,isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl;wherein such phenyl, naphthyl or heterocyclic group is optionallysubstituted with one to five groups selected from the group consistingof a C₁₋₆ branched or unbranched alkyl, phenyl, naphthyl, heterocycleselected from the group hereinabove described, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅ alkyl,naphthyl C₁₋₅ alkyl, halo, hydroxy, cyano, C₁₋₃ alkyloxy which mayoptionally be partially or fully halogenated, phenyloxy, naphthyloxy,heteraryloxy wherein the heterocyclic moiety is selected from the grouphereinabove described, nitro, amino, mono- or di-(C₁₋₃)alkylamino,phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclylmoiety is selected from the group hereinabove described, NH₂C(O), amono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₅ alkyl-C(O)-C₁₋₄ alkyl,amino-C₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl, amino-S(O)₂,di-(C₁₋₃)alkylamino-S(O)₂, R₄-C₁₋₅ alkyl, R₅-C₁₋₅ alkoxy, R₆-C(O)-C₁₋₅alkyl and R₇-C₁₋₅ alkyl(R₈)N;

b) a fused aryl selected from the group consisting of benzocyclobutanyl,indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl,benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclylselected from the group consisting of cyclopentenopyridine,cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine,cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine,cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline,cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole,cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene;wherein the fused aryl or fused heterocyclyl ring is substituted with 0to 3 groups independently selected from phenyl, naphthyl andheterocyclyl selected from the group consisting of pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,thienyl, furyl, isoxazolyl, and isothiazolyl, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,halo, cyano, C₁₋₃ alkyloxy which is optionally partially or fullyhalogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein theheterocyclyl moiety is selected from the group hereinabove described,nitro, amino, mono- or di-(C₁₋₃)alkylamino, phenylamino, naphthylamino,heterocyclylamino wherein the heterocyclyl moiety is selected from thegroup hereinabove described, NH₂C(O), a mono- or di-(C₁₋₃)alkylaminocarbonyl, C₁₋₄ alkyl-OC(O), C₁₋₅ alkyl-C(O)-C₁₋₄ branched orunbranched alkyl, an amino-C₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅alkyl, R₉-C₁₋₅ alkyl, R₁₀-C₁₋₅alkoxy, R₁₁-C(O)-C₁₋₅ alkyl, and R₁₂-C₁₋₅alkyl(R₁₃)N;

c) cycloalkyl selected from the group consisting of cyclopentanyl,cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl andbicycloheptanyl, which the cycloalkyl may optionally be partially orfully halogenated and which may optionally be substituted with one tothree C₁₋₃ alkyl groups;

d) C₅₋₇ cycloalkenyl, selected from the group consisting ofcyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein suchcycloalkenyl group may optionally be substituted with one to three C₁₋₃alkyl groups; and

e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl;

f) C₁₋₆ branched or unbranched alkyl which may optionally be partiallyor fully halogenated;

wherein

or R₁ and R₂ taken together may optionally form a fused phenyl orpyridinyl ring,

each R₈, R₁₃ is independently selected from the group consisting of:

hydrogen and C₁₋₄ branched or unbranched alkyl which may optionally bepartially or fully halogenated;

each R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁ and R₁₂ is independently selected fromthe group consisting of: morpholine, piperidine, piperazine, imidazoleand tetrazole;

m=0, 1, 2;

r=0, 1, 2;

t=0, 1, 2;

X=O or S and

physiologically acceptable acids or salts thereof.

A preferred subgeneric aspect of the invention comprises compounds ofthe formula(I) wherein Ar₂ is naphthyl, tetrahydronaphthyl, indanyl orindenyl.

A more preferred subgeneric aspect of the invention comprises compoundsof the formula(I) wherein Ar₂ is naphthyl.

A yet more preferred subgeneric aspect of the invention comprisescompounds of the formula (I), as described in the immediate previousparagraph, wherein:

Ar₁ is thiophene or pyrazole;

Ar₂ is 1 -naphthyl;

L is C₁₋₆ saturated or unsaturated branched or unbranched carbon chainwherein

one or more methylene groups are optionally independently replaced byO,N or S; and

wherein said linking group is optionally substituted with 0-2 oxo groupsand one or more C₁₋₄ branched or unbranched alkyl which may besubstituted by one or more halogen atoms;

R₁ is selected from the group consisting of C₃₋₁₀ alkyl branched orunbranched, cyclopropyl and cyclohexyl which may optionally be partiallyor fully halogenated and which may optionally be substituted with one tothree C₁₋₃ alkyl groups;

R₃ is selected from the group consisting of C₁₋₄alkyl branched orunbranched, cyclopropyl, phenyl, pyridinyl each being optionallysubstituted as described above, alkoxycarbonylalkyl; C₁₋₆alkyl branchedor unbranched; cyclopropyl or cyclopentyl optionally substituted asdescribed above.

A yet further preferred subgeneric aspect of the invention comprisescompounds of the formula (I), as described in the immediate previousparagraph, wherein Ar₁ is pyrazole.

A still yet further preferred subgeneric aspect of previous theinvention comprises compounds of the formula (I), as described in theimmediate paragraph, wherein L is C₁₋₅saturated carbon chain wherein oneor more methylene groups are optionally independently replaced by O,N orS; and

wherein said linking group is optionally substituted with 0-2 oxo groupsand one or more C₁₋₄ branched or unbranched alkyl which may besubstituted by one or more halogen atoms;

Particularly preferred embodiments of L are propoxy, ethoxy, methoxy,methyl, propyl, C₃₋₅ acetylene or methylamino each being optionallysubstituted are described herein.

A more particularly preferred embodiment of L is ethoxy optionallysubstituted.

The following compounds are representative of the compounds offormula(I):

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(cis-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-(methoxymethyl)morpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2-oxoethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2-methylethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-1-methylethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-thiomorpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-3-methylnaphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-piperidin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-acetylpiperidin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-thiazolidin-3-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyloxo)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(tetrahydropyran-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(N-methyl-2-methoxyethylamino)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxo-tetrahydrothiophen-3-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-methyl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-thiazolidin-3-yl-propyl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydopyran-2-yl-oxy)propyl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethyl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethenyl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(methoxymethyloxy)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)-3-methylpropyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)-3,3-dimethylpropyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)butyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(furan-2-ylcarbonyloxy)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(piperdin-1-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-methoxymethylmorpholin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-pyridin-4-yl-propoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-imidazol-1-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-benzimidazol-1-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dimethoxyphenyl)-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methylamino)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-carbonylamino)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-acetamido)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-3-yl-methylamino)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-3-yl-carbonylamino)naphthalen-1-yl]-urea;

1-[5-iso-Propyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-(Tetrahydropyran-3-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-cyclohexyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-(2,2,2-trifluoroethyl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-(1-methylcycloprop-1-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-ethoxycarbonyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-(1-methylcyclohex-1-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-benzyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-chlorophenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-butyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(ethoxycarbonylmethyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-methyl-3-(2-ethoxycarbonylvinyl)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-methyl-3-(morpholin-4-yl)methylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-methyl-3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(3-(2-morpholin-4-yl-ethyl)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(3-(tetrahydropyran-4-ylamino)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-(tetrahydropyran-4-ylamino)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-(3-benzylureido)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-chloropyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-dimethylaminomethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-iso-propyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(thiophen-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-cyclopentyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-iso-propyl-2H-pyrazol-3-yl]-3-[4-(tetrahyropyran-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(1-oxo-tetrahydrothiophen-3-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(thiophen-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridinyl-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-cyclopentyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-methylaminopyridin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(1-oxo-tetrahydothiophen-3-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(thiazolidin-3-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl-methoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-methylaminopyrimidin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methoxybenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methylaminobenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5-b]pyridin-1-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-[1,8]naphthyridin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-pyridin-3-yl-2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl-methoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(2-methylaminopyrimidin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(4-methoxybenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(4-methylaminobenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5-b]pyridin-1-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-[1,8]naphthyridin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl-methoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(2-methylaminopyrimidin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methoxybenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methylaminobenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-methyl-2H-pyrazol-3-yI]-3-[4-(2-(2-imidazo[4,5-b]pyridin-1-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-[1,8]naphthyridin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-yl)ethoxy)naphthalen-1-yl]-urea

and their physiologically acceptable acids or salts thereof.

Preferred compounds of the formula(I) are:

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(cis-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-(methoxymethyl)morpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2-oxoethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2-methylethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-1-methylethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-thiomorpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-ethoxy)-3-methylnaphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyloxo)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(tetrahydropyran-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxo-tetrahydrothiophen-3-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-methyl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethyl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)butyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(piperdin-1-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-methoxymethylmorpholin-4-yl)propyn-1-yl)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-pyridin-4-yl-propoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-imidazol-1-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dimethoxyphenyl)-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methylamino)naphthalen-1-yl]-urea;

1-[5-iso-Propyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-cyclohexyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-(2,2,2-trifluoroethyl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-(1-methylcycloprop-1-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-(1-methylcyclohex-1-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-chlorophenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-butyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-methyl-3-(morpholin-4-yl)methylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(4-methyl-3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-chloropyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6-dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyn-1-yl)naphthalen-1-yl]urea.

Particularly preferred compounds of the formula(I) are:

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea;

1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-ureaor

1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea.

Any compounds of this invention containing one or more asymmetric carbonatoms may occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. All such isomericforms of these compounds are expressly included in the presentinvention. Each stereogenic carbon may be in the R or S configuration,or a combination of configurations.

Some of the compounds of formula (I) can exist in more than onetautomeric form. The invention includes all such tautomers.

The term “aroyl” as used in the present specification shall beunderstood to mean “benzoyl” or “naphthoyl”.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester of a compound ofthis invention, or any other compound which, upon administration to apatient, is capable of providing (directly or indirectly) a compound ofthis invention, a pharmacologically active metabolite orpharmacologically active residue thereof.

The term “metabolite” shall be understood to mean any of the compoundsof the formula (I) which are capable of being hydroxylated or oxidized,enzymatically or chemically, as will be appreciated by those skilled inthe art. Nonlimiting examples of metabolites of the formula (I) areshown in the table below:

Structure Name

1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea

1-[5-tert-butyl-2-(3-hydroxy-4-methyl- phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]- urea

1-[5-tert-butyl-2-(4-hydroxymethyl- phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]- urea

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[2-(3-oxo-morpholino-4-yl)-ethoxy]- naphthalen-1-yl}-urea

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[2-(4-hydroxy-morpholin-4-yl)- ethoxy]-naphthalen-1-yl}-urea

1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1-yl]-urea

1-[5-tert-butyl)-2-(1-hydroxy-6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]- urea

1-[5-tert-butyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(4-hydroxy-morpholin-4-yl-ethoxy-naphthalen-1-yl}- urea

1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)-naphthalen-1- yl]-urea

1-[5-tert-butyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-hydroxy-2-pyridin-4-yl-ethoxy)-naphthalen-1-yl]-urea

1-[5-tert-butyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(1-hydroxy-pyridin-4-yl)-ethoxy]-naphthalen-1-yl}- urea

1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[2-(1-oxo-thiomorpholin-4-yl)-ethoxy]-naphthalen-1- yl}-urea

1-[5-tert-butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-3-{4-[2-(1-oxo-thiomorpholin-4-yl)-ethoxy]-naphthalen-1- yl}-urea

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[2-(1,3-dioxo-thiomorpholin-4-yl)- ethoxy]-naphthalen-1-yl}-urea

1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-2- methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]- urea

1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-{4-[2-(4-hydroxy-morpholin-4-yl)- ethoxy]-naphthalen-1-yl}-urea

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids.Other acids, such as oxalic acid, while not themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of this invention and theirpharmaceutically acceptable acid addition salts. Salts derived fromappropriate bases include alkali metal (e.g., sodium), alkaline earthmetal (e.g., magnesium), ammonium and N-(C₁-C₄ alkyl)₄ ⁺ salts.

In addition, the compounds of this invention include prodrugs ofcompounds of the formula (I). Prodrugs include those compounds that,upon simple chemical transformation, are modified to produce a compoundof formula (I). Simple chemical transformations include hydrolysis,oxidation and reduction. Specifically, when a prodrug of this inventionis administered to a patient, the prodrug may be transformed into acompound of formula (I), thereby imparting the desired pharmacologicaleffect.

GENERAL SYNTHETIC METHODS

The compounds of the invention may be prepared by Method A, B, or C asillustrated in Scheme I, preferably method C.

In Method A, a mixture of an aminoheterocycle of formula II and anarylisocyanate of formula III is dissolved in a non-protic, anhydroussolvent such as THF, either, toluene, dioxane or ethyl acetate. Thepreferred solvent is THF. The mixture is stirred at between 0-45° C.,preferably at 25° C., for 2-24 hr, and the volatiles are removed.Purification of the residue by recrystallization from an appropriatesolvent such as ethyl acetate/hexanes, ethyl acetate/methanol,THF/petroleum ether, ethanol/water. or by silica gel chromatography,using for example, hexanes and ethyl acetate as eluents, provides theproduct of formula I.

In Method B, an aminoheterocycle of formula II is dissolved in ahalogenated solvent, such as methylene chloride, chloroform ordichloroethane. The preferred solvent is methylene chloride. The mixtureis diluted with aqueous alkali, such as sodium bicarbonate or potassiumcarbonate, cooled in an ice bath and phosgene is added. The mixture isvigorously stirred for 5-30 min, with 10 min being preferable. Theorganic layer is dried, with agents such as MgSO₄ or Na₂SO₄, and thevolatiles removed to provide the corresponding isocyanate of formula II.The isocyanate and arylamine IV are mixed in a non-protic, anhydroussolvent such as THF, ether, toluene, dioxane, methylene chloride orethyl acetate. The preferred solvent is THF. The mixture is stirred atbetween 0-45° C., preferably at 25° C., for 2-24 hr, and the volatilesare removed. Purification of the residue by recrystallization or bysilica gel chromatography, as above, provides the product of formula I.

In Method C, an aminoheterocycle of formula II is dissolved in ahalogenated solvent, such as methylene chloride, chloroform ordichloroethane. The preferred solvent is methylene chloride. A suitablebase such as triethylamine may be added, followed by phenylchloroformate. The mixture is stirred at between 0-85° C., preferably atreflux temperature, for 2-24 hr, and the volatiles are removed providingcarbamate V. The carbamate and arylamine IV are mixed in a non-protic,anhydrous solvent such as THF, ether, toluene, dioxane, methylenechloride or ethyl acetate. The preferred solvent is THF. The mixture isstirred at between 0-110 C, preferably at reflux temperature, for 2-24hr, and the volatiles are removed. Purification of the residue as aboveprovides the product of formula I.

The method used to produce an aminoheterocycle of formula II will dependon the nature of the desired heterocycle. In general, intermediates offormula II can be made by methods known to those skilled in the art.Some general methods are illustrated in the schemes below. CompoundsG—NCO or G—NH₂ in Scheme I may be commercially available, or may beprepared by methods known to those skilled in the art. If G is aprecursor of Ar₂-L-Q ,the desired final product of formula (I) may beconstructed by methods known to those skilled in the art. Illustrativeexamples are contained in the Synthetic Examples section below.

Desired aminopyrazoles of formula XIII can be prepared as described inScheme II. A hydrazine of formula VIII, bearing substituent R₃, may beprepared by Method D or E. In Method D, an aryl bromide of formula VI isdissolved in a non-protic, inert solvent, such as THF, 1,4-dioxane ordiethyl ether, and cooled to low temperature under an inert atmosphere.The preferred temperature for the solution is −77° C. A strong basedissolved in a non-protic, inert solvent, such as hexanes, THF or ether,is added dropwise while maintaing a reaction temperature below 0° C. andpreferrably below −60° C. The preferred bases are alkyl lithium reagentsand the most preferred is sec-butyl lithium. After the addition of thebase, the reaction mixture is stirred for a period of time betweenthirty and ninety minutes or until all the starting aryl bromide hasbeen consumed. An excess of dialkyl azodicarboxylate is added whilemaintaining a reaction temperature below 0° C. and preferrably below−60° C. The preferred dialkyl azodicarboxylate is di-tert-butylazodicarboxylate. The reaction is stirred at cold temperatures andwarmed to room temperature after 0.5 hr to 2 hr. The reaction isquenched with the addition of water and the product extracted into anon-protic solvent, such as ethyl acetate, diethyl ether or chloroform.The organic layers are dried with agents such as MgSO₄ or Na₂SO₄ and thevolatiles removed. The residue is dissolved in protic solvents, such asmethanol or iso-propanol, cooled, preferably to 0-5° C. and treated withacid. Preferred acids are hydrochloric, hydrobromic, sulfuric andtrifluoroacetic. The most preferred is hydrochloric in gaseous form.After the addition of excess acid the mixture is heated at the refluxtemperature of the solvent until all starting material has beenconsumed. After cooling the product aryl-hydrazine of formula VIII saltis filtered and dried.

In Method E, an aryl amine bearing R₃ of formula VII is dissolved in aconcentrated aqueous acid such as hydrochloric, hydrobromic or sulfuricand cooled to ice bath temperatures. The most preferred acid ishydrochloric with concentrations between 3-8N with the most preferredconcentration of 6N. A nitrosating reagent in water is added dropwisewhile maintaining a cold temperature. The preferred temperature is 0-5°C. The preferred reagent is sodium nitrite. The reaction is stirredbetween 10-90 min and a reducing agent is added while maintaing coldtemperatures. The preferred temperature is 0-5° C. Reducing agentsinclude zinc, iron, samarium iodide and tin(II) chloride. The mostpreferred agent is tin(II) chlroride dissolved in aqueous hydrochloridewith a concentration of 3-8N with a most preferred concentration of 6N.The reaction is stirred between 0.5-3 hr and quenched with alkali to apH between 12-14. Alkali reagents include sodium hydroxide, potassiumhydroxide, lithium hydroxide and calcium hydroxide. The most preferredalkali reagent is potassium hydroxide. The aqueous solution is extractedwith a non-protic organic solvent, such as diethyl ether, chloroform,ethyl acetate and methylene chloride. The organic layers are dried withagents such as MgSO₄ and Na₂SO₄ and the volatiles removed to provide thearyl-hydrazine (VIII) which can be carried forward without furtherpurification.

A β-ketonitrile bearing R₁ (XII) may be prepared by Method F or G. InMethod F, a metal hydride, such as sodium hydride, potassium hydride orlithium hydride, is suspended in an anhydrous, inert, non-proticsolvent, such as diethyl ether, THF and dioxane, at temperatures between35-85° C. The most preferred metal hydride is sodium hydride and themost preferred solvent is THF at a temperature of 75° C. An alkyl ester,preferably a methyl ester (IX), and acetonitrile is dissolved in ananhydrous, inert, non-protic solvent, such as diethyl ether, THF ordioxane and added dropwise to the metal hydride suspension. Thepreferred solvent is THF. The mixture is kept at elevated temperaturesbetween 3-24 hours, cooled to room temperature and diluted with anon-protic solvent and aqueous acid. The organic layer is washed withwater and brine, dried, with agents such as MgSO₄ and Na₂SO₄, and thevolatiles removed to provide the β-ketonitrile (XII) which could be usedwithout further purification.

Alternatively, following Method G, a solution of a strong base, such asalkyl lithium reagents and metal amide reagents, such as n-butyllithium, sec-butyl lithium, methyl lithium and lithium diisopropylamide,in an anhydrous, inert, non-protic solvent, such as diethyl ether, THFand dioxane, is cooled below 0° C. The preferred base is n-butyllithium, the preferred solvent is THF and the preferred temperature is−77° C. A solution of cyanoacetic acid (X) in an anhydrous, inert,non-protic solvent, such as diethyl ether, THF and dioxane, and mostpreferrably THF, is added dropwise while maintaining a reactiontemperature below 0° C and preferrably at −77° C. The reaction isstirred between 10-45 min while warming to 0° C. The solution of thedianion of cyanoacetic is cooled to temperatures below −25° C. andpreferrably at −77° C. An alkyl acid chloride (XI) dissolved in ananhydrous, inert, non-protic solvent, such as diethyl ether, THF anddioxane, and most preferrably THF, is added. The reaction mixture iswarmed to 0° C. betweeen 10-30 min. and quenched with aqueous acid. Theproduct is extracted with an organic solvent, such as chloroform, ethylacetate, ether and methylene chloride. The combined organic extracts aredried, with agents such as MgSO₄ and Na₂SO₄, and the volatiles removedto provide the β-ketonitrile (XII) which could be used without furtherpurification.

The desired aminopyrazole (XIII) may then be prepared by Method H or I.In Method H, aryl hydrazine VIII and β-ketonitrile XII are mixed in anorganic solvent, such as toluene, ethanol, iso-propanol or t-butanol.The preferred solvent is ethanol. An acid, such as hydrochloric acid,p-toluene sulfonic acid or sulfuric acid, is added, The preferred acidis concentrated hydrochloric acid. The mixture is heated to temperaturesbetween 50-100° C., preferrably at 80° C., for 10-24 hr and cooled toroom temperature. The mixture is diluted with non-protic organicsolvent, such as ethyl acetate, ether, chloroform and methylenechloride, and washed with aqueous alkali, such as sodium bicarbonate andpotassium carbonate. The organic layer is dried, with agents such asMgSO₄ and Na₂SO₄, and the volatiles removed to provide a residue whichis purified by recrystallization or silica gel chromatography usinghexanes and ethyl acetate as eluents. The product-rich fractions arecollected and the volatiles removed to provide the desired amonopyrazole(XIII).

Alternatively, using Method I, aryl hydrazine VIII and β-ketonitrile XIIare mixed in an organic solvent, such as toluene, ethanol, iso-propanolor t-butanol. The preferred solvent is toluene. The mixture is heated atreflux temperatures for 3-24 hrs with azeotropic removal of water andworked up as described above providing the aminopyrazole XIII.

A general synthesis for desired aminothiophenes is illustrated in SchemeIII, Method J.

A mixture of 1-aryl-5-alkyl-butane-1,4-dione (XIV) and a sulfatingreagent, such as Lawesson's reagent or phosphorous (V) sulfide, andpreferrably Lawesson's reagent, is dissolved in a non-protic, anhydroussolvent, such as toluene, THF and dioxane. The preferred solvent istoluene. The mixture is heated at elevated temperatures and preferablyat a solvent-refluxing temperature for 1-10 hr. The volatiles areremoved and the residue is purified by silica gel chromatography usinghexanes and ethyl acetate as eluent. The product-rich fractions arecollected and the volatiles removed to provide the substituted thiopheneXV.

A mixture of substituted thiophene XV is dissolved in a solvent such asacetic anhydride or acetic acid. The preferred solvent is aceticanhydride. The mixture is cooled to 0-30° C. and preferrably to −10° C.A solution of concentrated nitric acid in a solvent such as aceticanhydride or acetic acid, with the preferred solvent being aceticanhydride is added while cooling 0-30° C. and preferrably to −10° C. Themixture is stirred between 10-120 min, poured onto ice and extractedwith a non-protic solvent such as diethyl ether, chloroform, ethylacetate or methylene chloride. The organic extracts are washed withaqueous alkali, dried with agents such as MgSO₄ and Na₂SO₄ and thevolatiles removed. The residue is purified by silica gel chromatographyusing hexanes and ethyl acetate as eluents. The product-rich fractionsare collected and the volatiles removed to provide the2-aryl-5-alkyl-3-nitrothiophene. The 2-aryl-5-alkyl-3-nitrothiophene isreduced by metals, such as iron, tin and zinc or catalytichydrogenation. The preferred reduction occurs with iron in acetic acidat temperatures between 50-110° C. and preferrably at 100° C. for 5-30min. After cooling to room temperature the reaction is diluted withwater, neutralized with alkali, such as sodium hydroxide, potassiumhydroxide, potassium carbonate or sodium bicarbonate, and extracted witha non-protic solvent such as diethyl ether, ethyl acetate or methylenechloride. The organic extracts are dried with agents such as MgSO₄ andNa₂SO₄ and the volatiles removed to provide the desired aminothiopheneXVI.

Other desired aminoheterocycles can be prepared by methods known in theart and described in the literature. The examples that follow areillustrative and, as recognized by one skilled in the art, particularreagents or conditions could be modified as needed for individualcompounds. Intermediates used in the schemes below are eithercommercially available or easily prepared from commercially availablematerials by those skilled in the art.

Scheme IV outlines a general scheme for desired aminofurans as describedby Stevenson et al. (J. Am. Chem. Soc., 1937, 59, 2525). An ethylaroylacetate (XVII) is dissolved in a non-protic solvent, such as etheror THF, and treated with a strong base, such as sodium, sodium ethoxideor sodium hydride, and the anion is reacted with a bromomethylalkylketone (XVIII) at low temperatures, such as 0° C. After stirringthe reaction until no starting material remains, it is poured onto coldwater and extracted with a non-protic solvent. The combined extracts aredried with agents such as MgSO₄ or Na₂SO₄. The diketo-ester (XIX) may becarried forward without further purification or purified by distillationor silica gel chromatography. The diketo-ester in a protic solvent, suchas ethanol, is heated in the presence of a mineral acid, such assulfuric or hydrochloric, for 5-10 hr. and extracted with a non-proticsolvent. The combined extracts are dried with agents such as MgSO₄ orNa₂SO₄. The furan-ester (XX) may be carried forward without furtherpurification or purified by distillation or silica gel chromatography.The furan-ester in a protic solvent, such as ethanol, is treated withhydrazine hydrate and the mixture heated for 2-5 days. The hydrazide isisloated as above and treated with hot formic acid and the resultingfuran-amine (XXI) purified by distillation or silica gel chromatography.

The synthesis of substituted 4-aminooxazoles may be achieved analogousto a procedure described by Lakhan et al. (J. Het. Chem., 1988, 25,1413) and illustrated in Scheme V. A mixture of aroyl cyanide (XXII),aldeyde (XXIII) and anhydrous ammonium acetate in acetic acid is heatedat 100-110° C. for 3-6 hr, cooled to room temperature and quenched withwater. Extraction by a non-protic solvent provides the product XXIVwhich can be carried forward without further purification or purified byrecrystallization or silica gel chromatography.

The synthesis of substituted 3-aminopyrroles (XXVIII) may be achieved ina manner analogous to Aiello et al., J. Chem. Soc. Perkins Trans. I,1981, 1. This is outlined in Scheme VI. A mixture of aryldioxoalkane(XXV) and amine (XXVI) in acetic acid is heated at 100-110° C. for 3-6hr and worked up in the usual manner. The product (XXVII) in acetic acidis treated with a nitrating agent, such as nitric acid and potassiumnitrate in concentrated sulfuric acid. The mixture is poured onto coldwater and extracted with a non-protic solvent. The combined extracts aredried with agents such as MgSO₄ and Na₂SO₄. Removal of the volatilesprovides the nitro-pyrrole which which may be carried forward withoutfurther purification or purified by recrystallization or silica gelchromatography. The nitro-pyrrole is reduced to the amine with iron inacetic acid or by catalytic hydrogenation using palladium on activatedcarbon. The aminopyrrole (XXVIII) may be carried forward without furtherpurification or purified by recrystallization or silica gelchromatography.

In an analogous fashion, a mixture of amine XXIX and3-aryl-2,5-dioxoalkane (XXX) in acetic acid is heated between 80-110° C.for 2-24 hr. The reaction is diluted with water and extracted with anorganic solvent. The combined extracts are dried with agents such asMgSO₄ or Na₂SO₄ and the volatiles removed. The resulting pyrrole istreated with a nitrating agent and subsequently reduced to XXXI asdescribed above. The product may be carried forward without furtherpurification or purified by recrystallization or silica gelchromatography. This process is illustrated in Scheme VII.

Substituted 5-aminothiazoles (XXXV) may be prepared in a manneranalogous to Gerwald et al., J. Prakt. Chem. 1973, 315, 539. Asillustrated in Scheme VIII, to a mixture of aminocyanide XXXII, aldehydeXXXIII and sulfur in an anhydrous solvent, such as ethanol and methanol,is added dropwise a base, such as triethylamine. The mixture is heatedat 50° C. for 1-3 hr. The mixture is cooled and the excess sulfurremoved. Acetic acid is added to neutralize the mixture and the solidcollected. The imine XXXIV is treated with acid, such as hydrchloric andtoluenesulfonic acid, in water and an organic solvent. After thestarting material is consumed the reaction is worked up and the productXXXV may be carried forward without further purification or purified byrecrystallization or silica gel chromatography.

A synthesis of substituted 2-aminothiophenes (XXXVII), analogous to aprocedure described by Gewald et al. (J. Prakt. Chem., 1973, 315, 539)is illustrated in Scheme IX. A mixture of disubstitutedthiophene-3-carboxylic acid (XXXVI) in a protic solvent, such as aceticacid, at a temperature of 0-50° C. is treated with a nitrating agent,such as nitric acid or potassium nitrate in concentrated sulfuric acid.After the starting material has been consumed the reaction is pouredonto ice and the product extracted with a non-protic solvent. Thecombined extracts are dried with agents such as MgSO₄ and Na₂SO₄ and thevolatiles removed. The nitrothiophene is reduced to the amine with ironin acetic acid or by catalytic hydrogenation using palladium onactivated carbon. The amino-thiophene may be carried forward withoutfurther purification or purified by recrystallization or silica gelchromatography.

1,5-Disubstituted-3-aminopyrazoles (XL) may be prepared as shown inScheme X, in a fashion analogous to the procedure described by Ege etal. (J. Het. Chem., 1982, 19, 1267). Potassium is added to anhydroust-butanol and the mixture cooled to 5° C. Hydrazine XXXVIII is added,followed by cyanodibromoalkane XXXIX. The mixture is heated at refluxingtemperatures for 3-10 hr. The mixture is cooled to room temperature andpoured onto ice water. The product is extracted with an organic solvent.The combined extracts are dried with agents such as MgSO₄ or Na₂SO₄ andthe volatiles removed. The product XL may be carried forward withoutfurther purification or purified by recrystallization or silica gelchromatography.

The synthesis of 2-amino-3,5-disubstituted thiophenes shown in SchemeXI, is done in a fashion analogous to Knoll et al., J. Prakt. Chem.,1985, 327, 463. A mixture of substitutedN-(3-aminothioacryloyl)-formamidine (XLI) and substituted bromide (XLII)in a protic solvent, such as methanol or ethanol, is heated, preferablyat a reflux temperature, for 5-30 min and cooled below room temperature.The product thiophene-imine is filtered and dried. The thiophene-imineXLIII is converted to the thiophene-amine (XLIV) by treatment withaqueous acid.

The synthesis of 1,4-disubstituted-2-aminopyrroles (XLVIII) may beaccomplished in a manner analogous to Brodrick et al. (J. Chem. Soc.Perkin Trans. I, 1975, 1910), and as illustrated in Scheme XII. Thepotassium salt of formylnitrile XLV in water is treated with amine XLVIand acetic acid and the mixture heated at 50-90° C. for 5-30 min. Theaminonitrile XLVII is collected by filtration upon cooling and then isstirred at room temperature with a base such as ethanolic potassiumethoxide for 2-5 hr and the volatiles removed. The residue is dilutedwith water and extracted with an organic solvent. The combined extractsare dried with agents such as MgSO₄ and Na₂SO₄ and the volatilesremoved. The product (XLVIII) may be carried forward without furtherpurification or purified by recrystallization or silica gelchromatography.

The preparation of 1,2-disubstituted-4-aminoimidazoles (L) by reductionof the corresponding nitro compound (XLIX), for example with iron inacetic acid or catalytic hydrogenation may be accomplished as describedby Al-Shaar et al. (J. Chem. Soc. Perkin Trans. I, 1992, 2779) andillustrated in Scheme XIII.

2,4-Disubstituted 5-aminooxazoles (LV) may be prepared in a manneranalogous to the procedure described by Poupaert et al. (Synthesis,1972, 622) and illustrated in Scheme XIV. Acid chloride LI is added to acold mixture of 2-aminonitrile LII and a base such as triethylamine in anon-protic solvent, such as THF, benzene, toluene or ether. Thepreferred temperature is 0° C. The mixture is stirred for 12-24 hr andwashed with water. The volatiles are removed and the product LIIItreated with ethylmercaptan and dry hydrogen chloride in dry methylenechloride for 5-30 min. The solid 5-imino-1,3-oxazole hydrochloride (LIV)is collected by filtration, dissolved in dry pyridine and the solutionsaturated with hydrogen sulfide during 4 hr at 0° C. The mixture isdiluted with an organic solvent and washed with water and dried. Removalof the volatiles provides the 5-amino-1,3-oxazole product (LV) which maybe carried forward without further purification or be purified by silicagel chromatography.

The synthesis of 1,4-disubstituted-2-aminopyrazoles may be accomplishedas illustrated in Scheme XV and described in Lancini et al., J. Het.Chem., 1966, 3, 152. To a mixture of substituted aminoketone (LVI) andcyanamide in water and acetic acid was added aqueous sodium hydroxideuntil pH 4.5 is reached. The mixture is heated at 50-90° C. for 1-5 hr,cooled and basicified with ammonium hydroxide. The product LVII iscollected by filtration and dried.

As in the cases described above, the synthesis of many otheraminoheterocycles useful as intermediates may be accomplished by methodssimilar to those described in the literature or known to those skilledin the art. Several additional examples are illustrated in Scheme XVI.2,5-Disubstituted-3-aminotriazoles (LVIII) have been described byPlenkiewicz et al. (Bull. Chem. Soc. Belg. 1987, 96, 675).1,3-Disubstituted-4-aminopyrazoles (LIX) have been described by Guarneriet al. (Gazz. Chim. Ital. 1968, 98, 569). Damany et al. (Tetrahedron,1976, 32, 2421) describe a 2-amino-3-substituted benzothiophene (LX). A3-aminoindole (LXI) is described by Foresti et al. (Gazz. Chim. Ital.,1975, 125, 151). Bristow et al. (J. Chem. Soc., 1954, 616) describe animidazo[1,2-a]pyridin-2-yl amine (LXII).

METHODS OF THERAPEUTIC USE

The compounds of the invention effectively block inflammatory cytokineproduction from cells. The inhibition of cytokine production is anattractive means for preventing and treating a variety of disordersassociated with excess cytokine production, e.g., diseases andpathological conditions involving inflammation. Thus, the compounds ofthe invention are useful for the treatment of such conditions. Theseencompass chronic inflammatory diseases including, but not limited to,osteoarthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn'sdisease, ulcerative colitis, psoriasis, graft versus host disease,systemic lupus erythematosus and insulin-dependent diabetes mellitus.The compounds of the invention can also be used to treat other disordersassociated with the activity of elevated levels of proinflammatorycytokines such as responses to various infectious agents and a number ofdiseases of autoimmunity such as rheumatoid arthritis, toxic shocksyndrome, diabetes and inflammatory bowel diseases unrelated to thoselisted above are discussed in the Background of the Invention.

In addition, the compounds of the invention being inhibitors of cytokineproduction are expected to block inducible cyclooxygenase (COX-2)expression. COX-2 expression has been shown to be increased by cytokinesand it is believed to be the isoform of cyclooxygenase responsible forinflammation (M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A, 1992,89, 4888.) Accordingly, the present novel compounds would be expected toexhibit efficacy against those disorders currently treated with COXinhibitors such as the familiar NSAIDs. These disorders include acuteand chronic pain as well as symptoms of inflammation and cardiovasculardisease.

As discussed in the Background of the Invention, IL-8 plays a role inthe influx of neutrophils into sites of inflammation or injury.Therefore, in a yet further aspect of the invention, the compounds ofthe invention may be useful in the treatment of diseases mediatedpredominantly by neutrophils such as stroke and myocardial infarction,alone or following thrombolytic therapy, thermal injury, adultrespiratory distress syndrome (ARDS), multiple organ injury secondary totrauma, acute glomerulonephritis, dermatoses with acute inflammatorycomponents, acute purulent meningitis or other central nervous systemdisorders, hemodialysis, leukopherisis, granulocyte transfusionassociated syndromes, and necrotizing entrerocolitis.

For therapeutic use, the compounds of the invention may be administeredin any conventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutic compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 5%, but more preferablyat least about 20%, of a compound of formula (I) (w/w) or a combinationthereof. The optimum percentage (w/w) of a compound of formula(I) mayvary and is within the purview of those skilled in the art.Alternatively, the compounds may be administered separately (eitherserially or in parallel). Separate dosing allows for greater flexibilityin the dosing regime.

As mentioned above, dosage forms of the compounds of this inventioninclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForns and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 10-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. As theskilled artisan will appreciate, lower or higher doses may be requireddepending on particular factors. For instance, specific dosage andtreatment regimens will depend on factors such as the patient's generalhealth profile, the severity and course of the patient's disorder ordisposition thereto, and the judgment of the treating physician.

SYNTHETIC EXAMPLES Example 1

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea:

A mixture of 4-methylphenyl hydrazine hydrochloride (10.0 g) and4,4-dimethyl-3 -oxopentanenitrile (8.67 g) in 150 mL ethanol and 7 mLconcentrated HCl was heated at reflux overnight, cooled to roomtemperature, basified to pH 12 with alkali and extracted with diethylether. The combined organic extracts were washed with brine and dried(MgSO₄). Removal of the volatiles in vacuo left a residue which wastriturated with hot petroleum ether (100 mL) and provided 12.5 g ofLXVII.

To a mixture of 4-amino-1-naphthol hydrochloride (LXIII) (172.1 g) in750 mL anhydrous THF at −78° C. was added dropwise over 60 min n-butyllithium (490 mL of a 1.60 M solution in hexanes). After the addition wascomplete the mixture was allowed to warm to room temperature and thencooled to −78° C. and di-tert-butyl dicarbonate ((BOC)₂O, 192 g) in 200mL THF was added over 20 min. The mixture was slowly warmed to roomtemperature and stirred for 3 h and most of the volatiles removed invacuo. The residue was diluted with ethyl acetate (1 L) and washed withwater (2×200 mL) and brine (200 mL) and filtered through celite anddried (MgSO₄). Removal of the volatiles in vacuo provided LXIV (226.1g).

A mixture of LXIV (0.397 g), 4-chloromethylpyridine hydrochloride (0.237g) and potassium carbonate (0.996 g, powdered) in 10 mL of acetonitrilewas heated at 80° C. for 6 hr, cooled to room temperature and dilutedwith water and ethyl acetate. The organic layer was washed with waterand brine and dried (MgSO₄). Removal of the volatiles in vacuo andpurification of the residue with flash chromatography using ethylacetate as the eluent provided 0.277 g LXV. A mixture of LXV (0.26 g)and HCl (0.6 mL of 4M HCl in dioxane) in 5 mL dioxane was stirred atroom temperature for 18 hr. Removal of the volatiles in vacuo providedLXVI.

As outlined in Method B (Scheme I), a mixture of LXVII (0.076 g) andphosgene (0.68 mL of a 1.93M solution in toluene) in 10 mL methylenechloride and 10 mL saturated sodium bicarbonate was stirred rapidly for15 min at 0-5° C. and the organic layer dried (MgSO₄). Removal of thevolatiles in vacuo left a residue which was added to a mixture of thedihydrochloride salt from above (0.104 g) andN,N-di-iso-propylethylamine (0.32 mL) in 5 mL anhydrous THF. The mixturewas stirred overnight and diluted with ethyl acetate and water. Theorganic layer was washed with water and brine and dried (MgSO₄). Removalof the volatiles in vacuo and purification of the residue with flashchromatography using ethyl acetate as the eluent and recrystallizationof the solid with water and ethanol gave 1, m.p. 132-133° C.

Example 2

1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)propyn-1-yl)naphthalen-1-yl]-urea:

Tetrahydro-2-(2-propynyloxy)-2H-pyran (LXVIII) (2.50 mL; 17.8 mmol) in100 mL anhydrous THF at −78° C. under inert atmosphere was treated withn-butyllithium (7.1 mL of a 2.5 M solution in hexanes), added viasyringe. The reaction was warmed to −20° C. and after 1 h stirring,tributyltin chloride (4.8 mL, 17.8 mmol) was added. After stirring at−20° C. for 1 h the reaction mixture was quenched with dilute NaHCO₃solution (˜75 mL) and extracted with ethyl ether (3×50 mL). The combinedethereal extracts were washed with brine and dried (MgSO₄). Afterfiltration all volatiles were removed in vacuo to produce LXIX as ayellow oil (4.7 g; 11.0 mmol or 62% yield).

A mixture LXVII (Example 1) (1.00 g; 3.76 mmol) and phosgene (5.6 mL ofa 2 M solution in toluene) and 4-bromonaphthylamine were reactedaccording to Method B (Scheme I and Example 1). The product was purifiedby trituration with hot heptane to afford LXX, mp 193-194° C. (1.75 g,3.67 mmol, 97% yield).

A mixture of LXX (970 mg, 2.03 mmol) and LXIX (1.31 g, 3.05 mmol) andBHT (50 mg) in 50 mL toluene at reflux under inert atmosphere wastreated with tetrakis(triphenylphosphine)palladium(0) (350 mg, 0.305mmol). The reaction mixture slowly changed color to black. After 40 minheating was stopped and, when the reaction mixture had cooled to ambienttemperature, a 5 M aqueous solution of KF (˜75 mL) was added. Themixture was stirred vigorously for 6 h, then the product was extractedwith ethyl acetate (3×50 mL). The combined organic extracts were washedwith brine and dried (MgSO₄), filtered and all volatiles were removed invacuo. Column chromatography, using 25% ethyl acetate in hexane eluant,followed by recrystallization from hot ethyl acetate/ hexane afforded780 mg of 2, mp 159-160° C., (1.45 mmol, 72% yield).

Example 3

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-pyridin-4-yl-propoxy)naphthalen-1-yl]-urea(3):

To a mixture of LXIV (Example 1) (0.51 g), 4-pyridinyl-1-propanol (0.76mL), and triphenylphosphine (1.5 g) in 10 mL anhydrous THF was addeddropwise diethyl azodicarboxylate (DEADC, 0.90 mL). After stirringovernight, the volatiles were removed in vacuo. Purification of theresidue by flash chromatography using 25% hexanes in ethyl acetate asthe eluent and concentration of the product-rich fractions in vacuoprovided ether LXXI. A mixture of LXXI (0.74 g) and HCl (5 mL, 4.0 M indioxane) in 10 mL anhydrous dioxane was stirred overnight. Collection ofthe precipitate by vacuum filtration provided LXXII. LXXVII (Example 1)(0.23 g), saturated NaHCO₃ (15 mL), dichloromethane (15 mL), phosgene(2.1 mL, 1.93M in toluene) and LXXII (0.32 g) were reacted according toMethod B (Scheme I and Example 1). Purification of the residue by flashchromatography using 25% hexanes in ethyl acetate as the eluent,concentration of the product-rich fractions in vacuo, followed byrecrystallization from ethyl acetate/methanol provided urea 3, m.p.205-207° C.

Example 4

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2-oxoethoxy)naphthalen-1-yl]-urea(4):

To a solution of morpholine (0.55 mL) in 5 mL of anhydrous ether at 0°C. was added chloroacetyl chloride. Collection of the precipitate byvacuum filtration provided amide LXXIII. A mixture of LXIV (Example 1)(0.44 g), LXXIII (0.30 g), and powered potassium carbonate (0.70 g) in10 mL acetonitrile was heated to 80° C. for 3.5 hours, cooled to roomtemperature, and diluted with ethyl acetate and water. The organic layerwas washed with water, saturated NaHCO₃, brine, dried (MgSO₄) and thevolatiles removed in vacuo. Purification of the residue by flashchromatography using 20% ethyl acetate in hexanes as the eluent andconcentration of the product-rich fractions in vacuo provided etherLXXIV. A mixture of LXXIV (0.26 g) and HCl (0.7 mL, 4.0M in dioxane) in4 mL anhydrous dioxane was stirred overnight. Collection of theprecipitate by vacuum filtration provided LXXV. LXVII (Example 1), (0.13g), and LXXV were reacted according to Method B (Scheme I and Example1). Trituration of the residue in hot methanol/water followed bycollection of the solid by vacuum filtration provided urea 4, m.p.240-241° C.

Example 5

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea(5):

A suspension of LXIV (Example 1) (5.0 g), powdered potassium carbonate(13.3 g) and 1-bromo-2-chloroethane (5.5 g) in 100 mL acetonitrile washeated at 80° C. overnight, cooled to room temperature and partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried (MgSO₄) and the volatiles removed in vacuo. Purification ofthe residue by flash chromatography using 25% ethyl acetate in hexanesas the eluent and concentration of the product-rich fractions in vacuoprovided ether LXXVI. A mixture of LXVI (2.0 g) and HCl (15 mL, 4.0 M indioxane) in 10 mL anhydrous dioxane was stirred overnight. Ether wasadded and the precipitate collected by vacuum filtration to affordLXXVII. As outlined in Method C, (Scheme I) a solution of LXXVII (1.6g), phenyl carbamate LXXVIII, prepared from LXVII, phenyl chloroformate(1.05 equiv), pyridine (3 equiv.) in THF, (2.3 g) anddiisopropylethylamine (3.1 g) in 10 mL anhydrous DMSO was stirred forone hour and diluted with ethyl acetate and water. The organic layer waswashed with water, 50% NaHCO₃, brine, dried (MgSO₄), and the volatilesremoved in vacuo. Purification of the residue by flash chromatographyusing 33% ethyl acetate in hexanes as the eluent, concentration of theproduct-rich fractions in vacuo, followed by trituration with 33% ethylacetate in hexanes provided LXXIX. A mixture of LXXIX (1.6 g) and sodiumiodide (5.0 g) in 10 mL acetone was heated at reflux for 4 days, cooledto room temperature and diluted with dichloromethane. The organics werewashed with water, dried (Na₂SO₄) and the volatiles removed in vacuo toprovide LXXX.

To a solution of thiomorpholine (0.50 g) in 25 mL of dichloromethane wasadded di-tert-butyldicarbonate. The mixture was stirred for 18 h at roomtemperature and the volatiles removed in vacuo. Recrystallization of theresidue from hexanes provided LXXXI. To a solution of LXXXI (0.40 g) in8 mL ethanol at 0° C. was added sodium periodate. The mixture wasstirred at 0° C. one hour, warmed to room temperature and stirred fivedays. The mixture was diluted with water and extracted withdichloromethane. The organic layer was washed with brine, dried (Na₂SO₄)and the volatiles removed in vacuo. Trituration of the residue withhexanes provided sulfoxide LXXXIII. To a solution of LXXXIII (0.15 g) in5 mL dichloromethane was added trifluoroacetic acid (TFA, 0.52 mL). Themixture was stirred 5 h and the volatiles removed in vacuo. The residuewas dissolved in methanol and HCl (4.0 M in dioxane) was added. Thevolatiles were removed in vacuo to provide sulfoxide LXXXIII. A mixtureof LXXXIII (0.05 g), LXXX (0.19 g), DIPEA (0.06 mL) in 2.5 mL DMF wasstirred overnight. The mixture was partitioned between ethyl acetate andwater and the aqueous layer extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried (MgSO₄) and the volatilesremoved in vacuo. Purification of the residue by flash chromatographyusing 9% methanol in ethyl acetate as the eluent and concentration ofthe product-rich fractions in vacuo provided urea 5, m.p. 205-207° C.

Example 6

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethenyl)naphthalen-1-yl]-urea(6):

A mixture of 4-bromoaminonaphthalene (5.0 g) anddi-tert-butyldicarbonate (5.9 g) in 100 mL toluene was heated at 70° C.for 15 hours, cooled to room temperature and the volatiles removed invacuo. The residue was dissolved in ethyl acetate, washed with 0.1M HCland brine, dried (MgSO₄) and the volatiles removed in vacuo.Recrystallization of the residue from hot petroleum ether providedLXXXIV. 4-Vinylpyridine (0.86 mL) was added to a suspension of LXXXIV(2.0 g) in 5 mL of triethylamine, followed by palladium (II) acetate(0.014 g) and tri-ortho-tolylphosphine (0.038 g). The mixture was heatedat 110° C. for four hours, cooled to room temperature, diluted withwater and ethyl acetate. The organic layer was washed with brine, dried(MgSO₄) and the volatiles removed in vacuo. Purification of the residueby flash chromatography using 50% ethyl acetate in hexanes as the eluentand concentration of the product-rich fractions in vacuo providednaphthalene LXXXV. A solution of LXXXV (0.34 g) in 10 mL TFA was stirredone hour and the volatiles removed in vacuo to provided LXXXVI. LXXXVIand LXVII (Example 1) were reacted according to Method B to provide 6,m.p. 203° C. (dec).

Example 7

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-(methoxymethyl)morpholin-4-yl)ethoxy)naphthalen-1-yl]-urea(7):

A mixture of LXXXVII (prepared by the method of Y. Jinbo et al; J. Med.Chem., 1994, 37, 2791) (0.044 g), LXXX (see Example 5) (0.15 g) andDIPEA (0.068 g) was stirred overnight, diluted with ether and water. Theorganic layer was washed with brine, dried (MgSO₄) and the volatilesremoved in vacuo. Purification of the residue by flash chromatographyusing a gradient of 1-4% methanol in ethyl acetate as the eluent andconcentration of the product-rich fractions in vacuo provided 7, m.p.85-90° C.

Example 8

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea(8):

A mixture of LXIV (Example 1) (0.464 g), 4-(2-chloroethyl)morpholinehydrochloride (0.3435 g) and powdered potassium carbonate (0.93 g) washeated in acetonitrile (15 mL) at 80° C. for 3 hours, cooled to roomtemperature and diluted with ethyl acetate and water. The organic layerwas washed with water, brine, dried (MgSO₄) and the volatile removed invacuo. Purification of the residue by flash chromatography using 12%hexanes in ethyl acetate as the eluent and concentration in vacuo of theproduct-rich fractions afforded LXXXVIII. A solution of LXXXVIII (0.511g) and HCl (1 mL of a 4M dioxane solution) in 5 mL dioxane was stirredat room temperature 20 hours. Removal of the volatiles in vacuo providedthe product LXXXIX, which was reacted with LXVII (Example 1) accordingto Method B to provide 8, m.p. 142-143° C.

Example 9

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea(9):

A slurry of diethyl malonate (42 mL) and sodium (4.71 g) was warmedslowly to 90° C. and stirred at 90° C. for 2 hours and 120° C. for 30min. before being cooled to room temperature. Toluene (200 mL) and2-chloro-5-nitropyridine (25.0 g) were added and the mixture was heatedat 110° C. for 1.5 hours and ambient temperature for 17 h. After removalof the volatiles in vacuo, 6 N HCl (200 mL) was added and the mixtureheated to reflux for 4 h and cooled to room temperature. The solutionwas neutralized with solid sodium carbonate, extracted with ethylacetate (6×100 mL), dried over solid magnesium sulfate, and concentratedto a dark solid. This material was purified by flash chromatographyusing 20% ethyl acetate in petroleum ether as the eluent. Concentrationin vacuo of the product-rich fractions afforded2-methyl-5-nitropyridine. A mixture of 2-methyl-5-nitropyridine (13.0 g)and 10% Pd on activated carbon (0.1 g) in 1,4-dioxane (150 mL) washydrogenated at 50 psi for 24 hours and filtered over celite. Removal ofthe volatiles in vacuo provided 2-methyl-5-aminopyridine. A solution ofthis compound (9.90 g) was dissolved in 6 N HCl (100 mL), cooled to 0°C., and vigorously stirred throughout the procedure. Sodium nitrite(6.32 g) in water (50 mL) was added. After 30 min, tin (II) chloridedihydrate (52.0 g) in 6 N HCl (100 mL) was added and the reaction slurrywas stirred at 0° C. for 3 hours. The pH was adjusted to pH 14 with 40%aqueous potassium hydroxide solution and extracted with ethyl acetate.The combined organic extracts were dried (MgSO₄) and removal of thevolatiles in vacuo provided hydrazine XC. A solution of XC (8.0 g) and4,4-dimethyl-3-oxopentanenitrile (10.0 g) in ethanol (200 mL) and 6 NHCl (6 mL) was refluxed for 17 hours and cooled to room temperature.Solid sodium hydrogen carbonate was added to neutralize the solution.The slurry was filtered and removal of the volatiles in vacuo provided aresidue which was purified by column chromatography using ethyl acetateas the eluent. Concentration in vacuo of the product-rich fractionsafforded XCI, which was reacted with LXXXIX (Example 8) according toMethod B to provide 9, m.p. 121-123° C.

Example 10

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]-urea(10)

To a solution of LXIV (Example 1) (0.962 g), 2-(pyridin-4-yl)ethanol(1.4 g) and triphenylphosphine (2.90 g) in THF (25 mL) was addeddropwise DEADC (1.8 mL). The mixture was stirred overnight and thevolatiles removed in vacuo. Purification of the residue with flashchromatography using ethyl acetate as the eluent and concentration invacuo of the product-rich fractions provided XCII. To a solution of XCII(1.4 g) in dioxane (15 mL) was added HCl (10 mL of a 4M dioxanesolution). The solution was stirred overnight and product XCIII wasfiltered and dried. This was reacted with XCI (Example 9) according toMethod B to provide 10, m.p. 189-190° C.

Example 11

1-[5-(1-methylcyclohex-1-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea(11):

To a solution of cyclohexane-1-methyl-1-carboxylic acid (1.31 g) in 5 mLmethylene chloride was added oxalyl chloride solution (5.5 mL of a 2.0 Mmethylene chloride solution) and 1 drop of anhydrous DMF. The mixturewas refluxed for 3 hours under inert atmosphere and cooled to roomtemperature. Cyanoacetic acid (1.57 g) in ethyl acetate was dried(MgSO₄) and the volatiles removed in vacuo. The residue and2,2-bipyridine (˜10 mg) in anhydrous THF (70 mL) was cooled to −70° C.and treated with n-BuLi (2.5 M in Hexanes) slowly, while allowing thereaction mixture to reach 0° C. When the red color persists at 0° C.(i.e. after 15.0 mL of n-BuLi solution), the solution was recooled to−70° C. and the acid chloride solution from above (9.21 mmol) was addedvia syringe in one portion. The mixture was warmed to room temperature,stirred 0.5 hours, poured onto 1 N aq. HCl (200 mL) and extracted withchloroform (3×100 mL). The combined organic layers were washed withsaturated aqueous NaHCO₃, brine and dried (MgSO₄). Removal of volatilesin vacuo provided a residue which was purified by column chromatographyusing hexanes and ethyl acetate as the eluent. Concentration in vacuo ofthe product-rich fractions provided XCIV. A solution of XCIV (0.80 g)and phenylhydrazine (0.48 mL) in toluene (5 mL) was heated withazeotropic removal of water overnight and the volatiles removed invacuo. Purification of the residue with flash chromatography using ethylacetate and hexanes as the eluent and concentration in vacuo of theproduct-rich fractions provided XCV, which was reacted with LXXXIX(Example 8) according to Method B to provide 11, m.p. 147-149° C.

Example 12

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methylamino)naphthalen-1-yl]-urea(12):

Isonicotinic acid (1.13 g) and DCC (2.5 g) were mixed together inmethylene chloride (80 mL) under an inert atmosphere and at roomtemperature. After 30 min 4-nitro-1-naphthylamine (1.70 g) was added tothis suspension as well as a catalytic amount of DMAP (˜50 mg). After 2days the suspension was filtered through Celite, the volatiles removedin vacuo and the residue purified by column chromatography to affordXCVI. A mixture of XCVI (0.299 g) in acetic acid (6 mL) was treated atroom temperature with a solution of tin chloride (1.55 g) in 6 mL ofconcentrated HCl. After stirring for 1.5 hours, the mixture was pouredslowly into 200 mL 15% aqueous NaOH solution and extracted with ethylacetate (3×100 mL). Drying (MgSO₄), removal of volatiles in vacuo andpurification of the residue by column chromatography using 5% methanolin ethyl acetate as the eluent afforded XCVII, which was reacted withLXVII (Example 1) according to Method B to provide XCVIII. To asuspension of XCVIII (0.101 g) in anhydrous THF (7 mL) at roomtemperature was added dropwise Red-Al (65% w/w solution in toluene; 0.27mL) under an inert atmosphere. The mixture was then refluxed for 1 h(dark red color), cooled and methanol was added dropwise until no moreevolution of H₂ was detected. Removal of most of the solvent in vacuoprovided a residue which was purified by column chromatography usinghexanes, 50% ethyl ecetate in hexanes and finally ethyl acetate as theeluents. Concentration of the product-rich fractions in vacuo furnishedsolid 12, m.p. 174-177° C.

Example 13

1-[5-tert-butyl-2-(3-(2-morpholin-4-yl-ethyl)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea(13):

A mixture of 3-nitrophenylacetic acid (5.02 g), morpholine (4.83 mL) andEDC (10.62 g) in 80 mL DMF at room temperature was stirred for 6 hoursand diluted with water and extracted with ethyl acetate. The combinedorganic extracts were washed with water and brine and dried (MgSO₄).Removal of the volatiles in vacuo provided XCIX. A mixture of XCIX (6.7g) and 10% Pd on carbon (0.1 g) in ethyl acetate (100 mL) washydrogenated at 45 psi for 15 hours and filtered over celite. Removal ofthe volatiles in vacuo furnished an amine (5.7 g) which was dissolved in6 N HCl (40 mL), cooled to 0° C., and vigorously stirred. Sodium nitrite(2.11 g) in water (5 mL) was added in a dropwise fashion. After 30 min,tin (II) chloride dihydrate (52.0 g) in 6 N HCl (100 mL) was added viaaddition funnel and the reaction slurry was stirred at 0° C. for 3hours. The pH was adjusted to 14 with 40% aqueous sodium hydroxidesolution and the solution extracted with ethyl acetate. The organiclayers were dried (MgSO₄). Removal of the volatiles in vacuo provided C.A solution of C (2 g) and 4,4-dimethyl-3-oxopentanenitrile (1.1 g) inethanol (80 mL) containing 6 N HCl (2 mL) was refluxed for 17 hours,cooled to room temperature and the pH was adjusted to 14 with 40%aqueous sodium hydroxide solution. The mixture was extracted with ethylacetate and the combined organic extracts were dried (MgSO₄). Removal ofthe volatile in vacuo provided CI. To a solution of CI (150 mg) in dryTHF (10 mL) at 0° C. was added dropwise a solution of LAH in ether (2.13mL of a 1M solution). The mixture was slowly warmed to 60° C., stirredfor 5 hours, cooled to room temperature and stirred 16 hours. Thereaction was quenched with the addition of 10% aqueous NaOH solutionuntil a neutral pH was achieved The mixture was extracted with ethylacetate and the combined organic extracts were dried (MgSO₄). Removal ofthe volatile in vacuo provided a residue which was purified by columnchromatography using ethyl acetate as the eluent. Concentration of theproduct-rich fractions in vacuo furnished CII, which was reacted withLXXXIX (Example 8) according to Method B to provide 13, as an oil.

Example 14

1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyl)naphthalen-1-yl]-urea(14):

A mixture of LXX (Example 2) (3.0 g), CIII (prepared by the procedure ofJ. W. Labadie et al; 1983, J. Org. Chem. 48, 4634) (3.0 g) andtetrakistriphenylphosphinepalladium (0.15 g) in 18 mL toluene was heatedto 100° C. for 30 min. Another 0.050 g of catalyst was added. Themixture was heated three hours, cooled to room temperature, diluted withether and washed with 5% NH₄OH, water, brine, dried (MgSO₄) and thevolatiles removed in vacuo. Purification of the residue by flashchromatography using 1% methanol in dichloromethane as the eluent andconcentration of the product-rich fractions in vacuo provided CIV. ToCIV (2.2 g), and hydrazine (4.9 g) in 50 mL ethanol and 10 mL THF at 0°C. was added dropwise a solution of sodium periodate (8.1 g) in 15 mLwater. The mixture was warmed to room temperature, stirred six hours,heated to 40° C. for two hours and diluted with dichloromethane, washedwith 1N sodium hydroxide, water, brine and dried (MgSO₄). Removal of thevolatiles in vacuo provided the saturated olefin. A mixture of thisalkane (2.1 g) and tetrabutylammonium flouride (14.4 mL, 1M in THF) andacetic acid (1.1 g) was stirred overnight, diluted with ethyl acetateand washed with water, brine, and dried (MgSO₄). Removal of thevolatiles in vacuo, purification of the residue by flash chromatographyusing 33% hexanes in ethyl acetate as the eluent and concentration ofthe product-rich fractions in vacuo provided the alcohol. To a solutionof this alcohol (0.60 g) in acetonitrile at 0° C. was addedtriphenylphosphine (0.52 g) then carbon tetrabromide (0.65 g). Themixture was stirred at room temperature for two days and the volatilesremoved in vacuo.

Purification of the residue by flash chromatography using 33% ethylacetate in hexanes as the eluent and concentration of the product-richfractions in vacuo provided CV. A mixture of CV (0.23 g), morpholine(0.039 g), KI (0.073 g) and DIPEA (0.1 mL) in DMF (3 mL) was stirred 6hours at room temperature and diluted with ether and water. The organiclayer was washed with brine and dried (MgSO₄). Removal of the volatilesin vacuo provided a residue which was purified by flash chromatographyusing ethyl acetate as the eluent. Concentration in vacuo of theproduct-rich fractions provided 14 which was recrystallized from hexanesand ethyl acetate, m.p. 147-149° C.

Table 1 illustrates additional compounds of the invention, which wereprepared by methods analogous to those described above.

TABLE 1

Ex. No. R₁ R₃ Q—L— m.p. ° C. 15 tert-butyl 2-Cl-pyridin-5-yl2-(morpholin-4-yl)ethoxy 123-125 16 tert-butyl 4-methyl-phenyl2-(imidazol-1-yl)ethoxy 201-202 17 tert-butyl 2-methoxy-pyridin-2-(morpholin-4-yl)ethoxy 108-110 5-yl 18 tert-butyl pyridin-3-yl2-(morpholin-4-yl)ethoxy 191-192 19 tert-butyl 4-Cl-phenyl2-(morpholin-4-yl)ethoxy 116-118 20 tert-butyl 4-methyl-phenylpyridin-3-ylmethylamino 137-140 21 tert-butyl 4-methyl-phenylmorpholin-4-yl-methyl  174 22 tert-butyl 4-methyl-phenyl2-(pyridin-4-yl)ethoxy 187-190 23 tert-butyl 4-methyl-phenyl3-(pyridin-3-yl)-n-propoxy 162-163 24 tert-butyl 4-methyl-phenylmorpholine-4-carbonyloxyethoxy 176-177 25 tert-butyl 4-methyl-phenyl2-(morpholin-4-yl)ethoxy 176-177 (Ar₂ = 3-methylnaphth-1-yl) 26tert-butyl 4-methyl-phenyl 2-(pyridin-4-yl)methyl 117-120 27 tert-butylmethyl 2-(morpholin-4-yl)ethoxy 201-202 28 tert-butyl 4-methyl-phenyl2-(thiomorpholin-4-yl)ethoxy 122-124 29 tert-butyl 4-methyl-phenyl2-(piperazin-1-yl)ethoxy  190 30 tert-butyl 4-methyl-phenyl2-(morpholin-4-yl)-n-propoxy 110-111 31 tert-butyl 4-methyl-phenyl2-(4-tetrahydropyran-4-yl)ethoxy 174-175 32 tert-butyl 4-methyl-phenyl3-(morpholin-4-yl)propyn-1-yl 120-121 33 tert-butyl 4-methyl-phenyl3-(piperidin-1-yl)propyn-1-yl 109-112 34 tert-butyl 4-methyl-phenyl4-[4-(tetrahydropyran-2-yloxy)but- 180-181 1-ynyl] 35 tert-butyl4-methyl-phenyl 2-(3,4-dimethoxyphenyl)ethoxy 183-184 36 tert-butyl4-methyl-phenyl (pyridine-4-carbonyl)amino >250 37 i-Pr phenyl2-(morpholin-4-yl)ethyl 177-178 38 CF₃CH₂ 4-methyl-phenyl2-(morpholin-4-yl)ethyl 176-178 39 3- phenyl 2-(morpholin-4-yl)ethyl155-156 tetrahydro- pyranyl 40 cyclohexyl phenyl2-(morpholino-4-yl)ethyl 191-192 41 tert-butyl n-butyl2-(morpholin-4-yl)ethyl 81-83 42 tert-butyl benzyl2-(morpholin-4-yl)ethyl 180-181 43 tert-butyl 4-methyl-3-2-(morpholin-4-yl)ethyl oil morpholin- 4-yl-methylphenyl 44 tert-butyl4-methyl-3- (2-morpholin-4-yl)ethyl oil C(O)NH₂- phenyl 45 tert-butyl4-methyl-3- 2-(morpholin-4-yl)ethyl oil (dimethyl)NCH₂- phenyl 46tert-butyl 4-methyl-phenyl pyridin-4-yl-oxy 47 1-methyl- 4-methyl-phenyl2-(morpholin-4-yl)ethoxy 146-8  cycloprop- 1-yl 48 tert-butyl4-methyl-phenyl 2-(morpholin-4-yl)ethoxy  99-100 Ar₂ = 5,6,7,8-tetrahydronaphthalene 49 tert-butyl 4-methyl-phenyl2-(trans-2,6-dimethyyl-morpholin- 137-139 4-yl)ethoxy 50 tert-butyl4-methyl-phenyl 2-(cis-2,6-dimethyl-morpholin-4- 153-154 yl)ethoxy 51tert-butyl 4-methyl-phenyl 2-(2-methoxymethyl-morpholin-4- 85-90yl)ethoxy 52 tert-butyl 4-methyl-phenyl 2-(1-oxo-thiomorpholin-4-205-207 yl)ethoxy 53 tert-butyl 4-methyl-phenyl2-(1-oxo-thiazolidin-3-yl)ethoxy 193-195 54 tert-butyl 4-methyl-phenyl5-methylamino-5-oxo-butyloxy 117-119 55 tert-butyl 4-methyl-phenyl5-amino-5-oxo-butyloxy foam 56 tert-butyl 4-methyl-phenyl5-(morpholin-4-yl)-5-oxo-butyloxy foam 57 tert-butyl 2-methyl-pyridin-5-pyridin-4-yl-thio yl

ASSESSMENT OF BIOLOGICAL PROPERTIES

Inhibition of TNF Production in THP Cells

The inhibition of cytokine production can be observed by measuringinhibition of TNFα in lipopolysaccharide stimulated THP cells. All cellsand reagents were diluted in RPMI 1640 with phenol red and L-glutamine,supplemented with additional L-glutamine (total: 4 mM), penicillin andstreptomycin (50 units/ml each) and fetal bovine serum (FBS, 3%) (GIBCO,all conc. final). Assay was performed under sterile conditions; onlytest compound preparation was nonsterile. Initial stock solutions weremade in DMSO followed by dilution into RPMI 1640 2-fold higher than thedesired final assay concentration. Confluent THP.1 cells (2×10⁶cells/ml, final conc.; American Type Culture Company, Rockville, Md.)were added to 96 well polypropylene round bottomed culture plates(Costar 3790; sterile) containing 125 μl test compound (2 foldconcentrated) or DMSO vehicle (controls, blanks). DMSO concentration didnot exceed 0.2% final. Cell mixture was allowed to preincubate for 30min, 37° C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS;1μg/ml final; Siga L-2630, from E.coli serotype 0111.B4; stored as1 mg/mlstock in endotoxin screened distilled H₂O at −80° C.). Blanks(unstimulated) received H₂O vehicle; final incubation volume was 250 μl.Overnight incubation (18-24 hr) proceeded as described above. Assay wasterminated by centrifuging plates 5 min, room temperature, 1600 rpm(400×g); supernatants were transferred to clean 96 well plates andstored −80° C. until analyzed for human TNFα by a commercially availableELISA kit (Biosource #KHC3015, Camarillo, Calif.). Data was analyzed bynon-linear regression (Hill equation) to generate a dose response curveusing SAS Software System (SAS institute, Inc., Cary, N.C.). Thecalculated IC50 value is the concentration of the test compound thatcaused a 50% decrease in the maximal TNFα production.

Representative compounds from the synthetic examples above and Table1were evaluated and all had IC₅₀<10 M in this assay.

Inhibition of Other Cytokines

By similar methods using peripheral blood monocytic cells, appropriatestimuli, and commercially available ELISA kits for a particularcytokine, inhibition of IL-1, GM-CSF, IL-6 and IL-8 was demonstrated byrepresentatives from the synthetic examples and Table 1.

What is claimed is:
 1. A Compound of the formula (I):

wherein Ar₁ is thiophene which may be substituted by one or more R₁, R₂or R₃; Ar₂ is: naphthyl optionally substituted with one to three R₂groups; L is a C₁₋₁₀ saturated or unsaturated branched or unbranchedcarbon chain; wherein one or more methylene groups are optionallyindependently replaced by O, N or S; and wherein said linking group isoptionally substituted with 0-2 oxo groups and one or more C₁₋₄ branchedor unbranched alkyl which may be substituted by one or more halogenatoms; Q is selected from the group consisting of: a) pyrimidine,pyridazine, imidazole, benzimidazole, naphthyridine,oxazo[4,5-b]pyridine and imidazo[4,5-b]pyridine, which are optionallysubstituted with one to three groups selected from the group consistingof halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, mono- or di-(C₁₋₃alkyl)amino, C₁₋₆ alkyl-S(O)_(m) and phenylamino wherein the phenyl ringis optionally substituted with one to two groups selected from the groupconsisting of halogen, C₁₋₆ alkyl and C₁₋₆ alkoxy; b) morpholine,thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone,piperidine, piperidinone and tetrahydropyrimidone, which are optionallysubstituted with one to three groups selected from the group consistingof C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, mono- or di-(C₁₋₃ alkyl)amino-C₁₋₃alkyl, phenylamino-C₁₋₃ alkyl and C₁₋₃ alkoxy-C₁₋₃ alkyl; R₁ is selectedfrom the group consisting of: a) C₃₋₁₀ branched or unbranched alkyl,which may optionally be partially or fully halogenated, and optionallysubstituted with one to three phenyl, naphthyl or heterocyclic groupsselected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyland isothiazolyl; each such phenyl, naphthyl or heterocycle selectedfrom the group hereinabove described, being substituted with 0 to 5groups selected from the group consisting of halogen, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl, hydroxy, cyano, C₁₋₃ alkyloxy whichis optionally partially or fully halogenated, NH₂C(O) anddi(C₁₋₃)alkylaminocarbonyl; b) C₃₋₇ cycloalkyl selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl,cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl,which may optionally be partially or fully halogenated and which mayoptionally be substituted with one to three C₁₋₃ alkyl groups, or ananalog of such cycloalkyl group wherein one to three ring methylenegroups are replaced by groups independently selected from O, S,CHOH, >C═O, >C═S and NH; c) C₃₋₁₀ branched alkenyl which may optionallybe partially or fully halogenated, and which is optionally substitutedwith one to three C₁₋₅ branched or unbranched alkyl, phenyl, naphthyl orheterocyclic groups, with each such heterocyclic group beingindependently selected from the group consisting of pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl,naphthyl or heterocyclic group being substituted with 0 to 5 groupsselected from halogen, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl,bicyclohexanyl and bicycloheptanyl, hydroxy, cyano, C₁₋₃ alkyloxy whichis optionally partially or fully halogenated, NH₂C(O), mono- ordi(C₁₋₃)alkylaminocarbonyl; d) C₅₋₇ cycloalkenyl selected from the groupconsisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl,wherein such cycloalkenyl group may optionally be substituted with oneto three C₁₋₃ alkyl groups; e) cyano; and, f) methoxycarbonyl,ethoxycarbonyl and propoxycarbonyl; R₂ is selected from the groupconsisting of: a C₁₋₆ branched or unbranched alkyl which may optionallybe partially or fully halogenated, acetyl, aroyl, C₁₋₄ branched orunbranched alkoxy, which may optionally be partially or fullyhalogenated, halogen, methoxycarbonyl and phenylsulfonyl; R₃ is selectedfrom the group consisting of: a) a phenyl, naphthyl or heterocyclicgroup selected from the group consisting of pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl,indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl,naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl;wherein such phenyl, naphthyl or heterocyclic group is optionallysubstituted with one to five groups selected from the group consistingof a C₁₋₆ branched or unbranched alkyl, phenyl, naphthyl, heterocycleselected from the group hereinabove described, C₁₋₆ branched orunbranched alkyl which is optionally partially or fully halogenated,cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl,bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C₁₋₅ alkyl,naphthyl C₁₋₅ alkyl, halo, hydroxy, cyano, C₁₋₃ alkyloxy which mayoptionally be partially or fully halogenated, phenyloxy, naphthyloxy,heteraryloxy wherein the heterocyclic moiety is selected from the grouphereinabove described, nitro, amino, mono- or di-(C₁₋₃)alkylamino,phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclylmoiety is selected from the group hereinabove described, NH₂C(O), amono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₅ alkyl-C(O)-C₁₋₄ alkyl,amino-C₁₋₅ alkyl, mono- or di-(C₁₋₃) alkylamino-C₁₋₅ alkyl, amino-S(O)₂,di-(C₁₋₃)alkylamino-S(O)₂, R₄-C₁₋₅ alkyl, R₅-C₁₋₅ alkoxy, R₆—C(O)-C₁₋₅alkyl and R₇-C₁₋₅ alkyl(R₈)N; b) a fused aryl selected from the groupconsisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl,tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or afused heterocyclyl selected from the group consisting ofcyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine,cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine,cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline,cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline,cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole,cyclohexanobenzimidazole, cyclopentanobenzoxazole,cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole,cyclopentanothiophene and cyclohexanothiophene; wherein the fused arylor fused heterocyclyl ring is substituted with 0 to 3 groupsindependently selected from phenyl, naphthyl and heterocyclyl selectedfrom the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, and isothiazolyl, C₁₋₆ branched or unbranched alkyl which isoptionally partially or fully halogenated, halo, cyano, C₁₋₃ alkyloxywhich is optionally partially or fully halogenated, phenyloxy,naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selectedfrom the group hereinabove described, nitro, amino, mono- ordi-(C₁₋₃)alkylamino, phenylamino, naphthylamino, heterocyclylaminowherein the heterocyclyl moiety is selected from the group hereinabovedescribed, NH₂C(O), a mono- or di-(C₁₋₃)alkyl aminocarbonyl, C₁₋₄alkyl-OC(O), C₁₋₅ alkyl-C(O)-C₁₋₄ branched or unbranched alkyl, anamino-C₁₋₅ alkyl, mono- or di-(C₁₋₃)alkylamino-C₁₋₅ alkyl, R₉-C₁₋₅alkyl,R₁₀-C₁₋₅ alkoxy, R₁₁—C(O)-C₁₋₅ alkyl and R₁₂-C₁₋₅alkyl(R₁₃)N; c)cycloalkyl selected from the group consisting of cyclopentanyl,cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl andbicycloheptanyl, which the cycloalkyl may optionally be partially orfully halogenated and which may optionally be substituted with one tothree C₁₋₃ alkyl groups; d) C₅₋₇ cycloalkenyl, selected from the groupconsisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl,wherein such cycloalkenyl group may optionally be substituted with oneto three C₁₋₃ alkyl groups; and e) acetyl, aroyl, alkoxycarbonylalkyl orphenylsulfonyl; f) C₁₋₆ branched or unbranched alkyl which mayoptionally be partially or fully halogenated; R₁ and R₂ taken togethermay optionally form a fused phenyl or pyridinyl ring, each R₈, R₁₃ isindependently selected from the group consisting of: hydrogen and C₁₋₄branched or unbranched alkyl which may optionally be partially or fullyhalogenated; each R₄, R₅, R₆, R₇, R₉, R₁₀, R₁₁ and R₁₂ is independentlyselected from the group consisting of: morpholine, piperidine,piperazine, imidazole and tetrazole; m=0, 1 or 2; r=0, 1 or 2; t=0, 1 or2; X=O or S and physiologically acceptable acids or salts thereof. 2.The compound according to claim 1 wherein: Ar₂ is1-naphthyl; L is C₁₋₆saturated or unsaturated branched or unbranched carbon chain wherein oneor more methylene groups are optionally independently replaced by O,N orS; and wherein said linking group is optionally substituted with 0-2 oxogroups and one or more C₁₋₄ branched or unbranched alkyl which may besubstituted by one or more halogen atoms; R₁ is selected from the groupconsisting of C₃₋₁₀ alkyl branched or unbranched, cyclopropyl andcyclohexyl which may optionally be partially or fully halogenated andwhich may optionally be substituted with one to three C₁₋₃ alkyl groups;R₃ is selected from the group consisting of cyclopropyl, cyclopentyl,phenyl, pyridinyl alkoxycarbonylalkyl and C₁₋₆alkyl branched orunbranched, each optionally substituted as described in claim
 1. 3. Acompound according to claim 2 wherein L is C₁₋₅ saturated carbon chainwherein one or more methylene groups are optionally independentlyreplaced by O, N or S; wherein said linking group is optionallysubstituted with 0-2 oxo groups and one or more C₁₋₄ branched orunbranched alkyl which may be substituted by one or more halogen atoms;and X=O.
 4. The compound according to claim 3 wherein L is propoxy,ethoxy or methoxy each being optionally substituted with 0-2 oxo groupsand one or more C₁₋₄ branched or unbranched alkyl which may besubstituted by one or more halogen atoms.
 5. The compound according toclaim 4 wherein L is ethoxy optionally substituted with 0-2 oxo groupsand one or more C₁₋₄ branched or unbranched alkyl which may besubstituted by one or more halogen atoms.
 6. The compound according toclaim 3 wherein L is methyl or propyl each being optionally substitutedwith 0-2 oxo groups and one or more C₁₋₄ branched or unbranched alkylwhich may be substituted by one or more halogen atoms.
 7. The compoundaccording to claim 3 wherein L is C₃₋₅acetylene optionally substitutedwith 0-2 oxo groups and one or more C₁₋₄ branched or unbranched alkylwhich may be substituted by one or more halogen atoms.
 8. The compoundaccording to claim 3 wherein L is methylamino optionally substitutedwith 0-2 oxo groups and one or more C₁₋₄ branched or unbranched alkylwhich may be substituted by one or more halogen atoms.
 9. A method oftreating an inflammatory disease which comprises administering to apatient in need of such treatment a therapeutically effective amount ofa compound according to claim
 1. 10. The method according to claim 9wherein the inflammatory disease is selected from the groups consistingof rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome,Crohn's disease, ulcerative colitis, psoriasis, graft versus hostdisease, systemic lupus erythematosus and insulin-dependent diabetesmellitus.
 11. A method of treating an autoimmune disease which comprisesadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 1. 12. The methodaccording to claim 11 wherein the autoimmune disease is selected fromthe groups consisting of as toxic shock syndrome, osteoarthritis,diabetes and inflammatory bowel diseases.
 13. A method of treating adisease or condition selected from the group consisting of: acute andchronic pain, contact dermatitis, atherosclerosis, glomerulonephritis,reperfusion injury, bone resorption diseases, asthma, stroke, myocardialinfarction, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, dermatoses with acuteinflammatory components, acute purulent meningitis, necrotizingentrerocolitis, syndromes associated with hemodialysis, septic shock,leukopherisis and granulocyte transfusion, said method comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 1. 14. A process ofmaking a compound of the formula(I) according to claim 1

wherein X is O and Ar₁, Ar₂, L and Q are defined as in claim 1,comprising: (a) reacting and aminoheterocycle of the formula (II):Ar₁—NH₂ with phenyl chloroformate to form a carbamate compound of theformula (V):

(b) reacting the carbamate of the formula (V) from step (a) with anarylamine of the formula (IV):

to form a compound of the formula (I).
 15. A pharmaceutical compositioncomprising a pharmaceutically effective amount of a compound accordingto claim 1.